Metabolic deactivation of hexavalent chromium mutagenicity

Abstract

Hexavalent chromium compounds (sodium dichromate, potassium chromate, chromic acid, basic zinc chromate and basic lead chromate) were found to be mutagenic for his − strains of S. typhimurium by inducing both frameshifts and base-pair substitutions. However, addition of either microsomal fractions from rat liver or of human erythrocyte lysates resulted in a complete loss of mutagenicity. As confirmed by chemical analysis, reversal of mutagenicity could be ascribed to reduction of the metal to the inactive trivalent form through a simple oxido-reductive reaction. In fact, reducing agents (ascorbic acid and sodium sulfite) and metabolites (GSH, DPNH and TPNH, either directly tested or obtained by mixing G6PD with S-9 mix) prevented hexavalent chromium mutagenicity, whereas an oxidizing agent (potassium permanganate) totally inhibited reversal of mutagenicity by liver and erythrocyte preparations. Enzymic conversion appeared to be involved in deactivation processes through a large production of TPNH via the hexose monophosphate oxidative pathway and other ancillary systems. On the other hand, microsomal preparations from rat lung displayed an extremely poor inactivating effect on chromium mutagenicity, and those from rat muscle, as well as human serum or plasma, were ineffective. These findings could bear relevance for the elective localization of chromium-induced tumors in human lung and could account for the results of animal carcinogenicity tests, which generally showed the development of tumors, but only at implant sites.